Quaternary ammonium halides of benzhydryl ether derivatives



Patented Mar. 15, 1949 QUATERNARY AMMONIUM HALIDES OF BENZHYDRYL ETHER DERIVATIVES George Rieveschl, J r., Grosse Pointe Woods, Mich, assignor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application April 8, 1946, Serial No. 660,407

10 Claims. 1

This invention relates'to new quaternary ammoniumxhalidesandto methodsof obtaining the same; More particularly, the invention relates tozcompounds of the general formula,

m oH-o-oHiomN-m U R. H

where R1 and 3.2 are the same ordifferent substituents and represent hydrogen, an alkyl radical containing 1 or 2 carbon atoms or an alkoxy radical containing 1 or 2 carbon atoms, R3 and R4 are the same or difierentalkyl radicals containing 1 to 3 carbon atoms inclusive or R3 and R4 taken with N may be a saturated six-membered heterocyclic ring such as piperidine, a methyl substituted piperidine, morpholine, a methyl substituted. morpholine, thiomorpholine andthe-like, R5 isa hydrogen, .phenyl or a lower alkyl radical, R6 is an. alkyl radical containingl to, 10 carbon atoms inclusive, a phenyl radical, a phenyl radical substituted on a carbon thereof by. ahalogen atom or a lower alkyl or lower alkoxy radical, an aralkyl radical, an aralkyl radical wherein the phenyl ring is substituted on a carbon atom thereof by a halogenatom or a lower alkyl orlower alkoxy radical and X is a chlorine, bromine oriodine atom.

I'have' found that the new compounds of the presentinventionmay be prepared in almost quantitative yields by the reaction of a halo acetic acid ester compound of the formula,

with .all-aminoethyl benzhydryl ether compound of the formula,

. R5 CH- 0-0 HaCHnN where R1, R2, R3. R4, R5, R6 and X have the same significance as given above.

The reaction is preferably carried out in a substantially anhydrous, inert organic solvent. Some examples of the solvents which I have found to" be suitable as reaction .mediums: are ether, chloroform; carbon tetrachloride; benzene, toluene=,'.xylne,'- methanol,.ethanol, isopropanol, n-

propanol, acetone, ethyl acetate, acetonitrile, nitromethane and the like. In most instances, the product separates from the reaction mixture in,

crystalline form and requires little or no furtherv purification. However, when an alcohol such as methanol, ethanol, isopropanol and the like is; used as a solvent, the reaction product is soluble in the solvent if too much solvent has been used.

In this case the product may either be crystallized,

directly from the reaction mixture by evaporation of some of the solvent or it may be precipitated from the reaction mixture by the addition of another solvent in which the product is in-- soluble, e. g. ether, acetone, chloroform, ethyl acetate and the like.

The compounds of the present invention are very useful and safe curariform agents. The safety margin, e. g. difference between the therapeutic and toxic doses, of these compounds is much greater than that of the naturalcurare alkaloids such as d-tubocurarine chloride. These new compounds find particular use as an adjunct to anesthesia in abdominal surgery andalso in the inhibition of spasms of the skeletal muscles during electric, metrazole or insulin shock treatments of certain types of insanity. They may be administered by the parenteral routes. The parenteral dose is only about 20 to 40 mg. For

example, the compound shown in Example. 2,v

B benzhydryloxyethyl dimethyl carbobutoxy methyl ammonium chloride is customarily administered in a dose of 30 mg. by the parenteral route, preferably intravenously.

The invention is illustrated by the following examples.

Example 1. p-Benzhydrylomethyldimethylcarbethorymethyl ammonium bromide CEO-OHZOHzN-CH: 0 H2O OOHQOH, I

184 g. of ethyl bromoacetate is added'slowly with stirring to a refluxing solution of 255 g. of B-dimethylaminoethyl benzyhydryl ether in 500 cc. of ethyl acetate. After all the bromo ester has been added the reaction mixture isrefluxed for one and one-half hours, cooled and the crys-' talline p-benzhydryloxyethyl dimethyl carbetheoxymethyl ammonium bromide removed by fil'.

tration. The crude product is washed with ethyl acetate and purified by recrystallization from;

3 absolute ethanol-ethyl acetate mixture; M. P. 178-179 C.

By using an equivalent amount of ethyl chloroacetate in the above procedure instead of the ethyl bromoacetate, one obtains ,B-benzhydryloxyethyldimethylcarbethoxymethyl ammonium chloride; M. P. 177 C. Likewise, when one uses the methyl ester of chloracetic acid in this procedure, p benzhydryloxyethyldimethylcarbomethoxymethyl ammonium chloride, M. P. 163.5- 164.5 C., is obtained.

Example 2.p-Benzhydryloxyethyldimethyl carbobutoxymethyl ammonium chloride Cl CH:

CHO CHzCHgN-CH3 v/ i O Example 3.e-Benzhydryloxyethyl dimethyl a-carbethoxyethyl ammonium bromide Bl CH5 137 g. of ethyl m-bromopropionate is added dropwise to a stirred and refluxing solution of 175 g. of ,B-dimethylaminoethyl benzhydryl ether in500 cc. of di-isopropyl ether. After all the halo ester has been added the mixture is refluxed for two hours, cooled and the crystalline product removed by filtration. The crude p-benzhydryloxyethyl dimethyl a-carbethoxyethyl ammonium bromide is washed with several portions of diisopropyl ether and purified by recrystallization from absolute ethanol-ethyl acetate mixture; M. P. 152-153 C.

Example 4. fl Benzhydryloxyethyl dimethyl a-phenylcarbethoxymethyl ammonium bromide Br OH:

ono-omomN-om 0 CY lee 158 g. of ethyl bromophenylacetate is added slowly to a stirred solution of 150 g. of fi-dimethylaminoethyl benzhydryl ether in 500 cc. of to]- uene. After the addition has been completed the mixture is warmed on a steam bath for two hours, cooled and the white crystalline product removed by filtration. The product, fi-benzhy dryloxyethyl dimethyl a phenylcarbethoxymethyl ammonium bromide, is washed with ether and purified by recrystallization from absolute ethanol; M. P. 1385-1395 C.

Example 5.4- (fi-Benehydryloxyethy l) -4-carbethoxymethyl morpholimum bromide Br onion:

92 g. of ethyl bromoacetate is added slowly to a stirred and refluxing solution of 148 g. of p-N- morpholinylethyl benzhydryl ether in 300 cc. of ethyl acetate and the resulting mixture heated on a steam bath for one hour. The reaction mixture is cooled and the white crystalline 4-(18- benzhydryloxyethyl)-4-carbethoxymethyl morpholinium bromide removed by filtration and purified by recrystallization from absolute ethanol-ethyl acetate mixture; M. P. 194-195 C.

Example 6'.1 b-Benzhydryloxyethyl) -1 -carbon-butoxymethyl piperidinium chloride C1 CHzCHz CHOCH2CH21 V CH2 CHgCi (EH20 I O CHECHZCHQOHZ A mixture consisting of 148 g. of fi-N-piperidylethyl benzhydryl ether and 83 g. of n-butyl chloro acetate in 300 cc. of n-butanol is stirred and heated on a steam bath for two and one- After the reaction mixture has cooled, 1 liter of ether is added and the crude I-(fl-benzhydryloxyethyl) 1 carbo-n-butoxyhalf hours.

methyl piperidinium chloride removed by filtra-" tion. The product is washed well with ether and;

purified by recrystallization from absolute etha- I;

nolacetone mixture.

By using an equivalent amount of p-N-3 I methylpiperidylethyl benzhydryl ether in the above procedure, one obtains 1- (fl-benzhydryloxyethyl) -l-carbo-n-butoxymethyl methylpiperidinium chloride.

1 (p benzhydryloxyethyl) 1 carbethoxy methyl piperidinium bromide, M. P. 176-8 C., is obtained by reacting ethyl bromoacetate with p-N-pipeidylethyl benzhydryl ether in the manner described above.

Example 7.-p -4,4'-dimethylbenzhydryzbxymiii di-n-prop'yl carbo-n-octyloxymethyl ammo-" nium iodide GHQ I onlor con3 ono-onzon'zN A CHzOBgCH; I .0

164 g. of n-octyl iodoacetate is added drop-Q wise to a stirred solution of 156 g. of yfl-di-ni;

propylaminoethyl 4,4 -dimethylbe'nzhydry1; ether" 5. in 500cc. of toluene. After the additionis com plate the mixture is stirred for twohours at room'- temperature and then warmed on a steam bath for one-half hour. The mixture is cooled and the white crystalline product collected and washed with ether. If desired the crude product may be purified by recrystallization from absolute ethanol-ether mixture.

fi-Benzhydryloxyethyl dimethyl carbo-Z-ethylhexyloxymethyl ammonium chloride, M. P, 128- 9 C., may be obtained in a similar manner by using equivalent quantities of fi-dimethylaminoethyl benzhydryl ether and Z-ethylhexyl chloroa etate.-

Ezample 8.- 3 2 methomybenzhydryloxyethyl methylethyl carbomethowymethyl ammonium bromide Br CH CEO-GHZCHgN CHzCH;

CHQC

OCHS

A, mixture consisting of 135 g. of il-methylethylaminoethyl 2 methoxybenzhydryl' ether and '77 g. of methyl bromoacetate in 200 cc. of dry methanol is refluxed for twoand one-half hours, cooled and the reaction mixture diluted with ether. The crude product is collected. washed with ether and purified by recrystallization from methanolacetone mixture.

Example 9.o-benzhydryloryethyl dimethyl carbohenzylorymethyl ammonium chloride 102 g. of benzyl chloroacetate is added; slowly to. a refluxing solution of 128 g, of fi-dimethylaminoethyl benzhydryl ether in 3001 cc. of, benzene and the resulting mixture refluxed for one and a half hours. The mixture is cooled, and the crystalline product, fi-benzhydryloxyethyl dimethyl oarbobenzyloxymethyl ammonium chloride, removed b filtration. The crude product after recrystallization from ethanol-ethyl acetate mixture melts at 17 l-2 C.

The various aminoethyl benzhydryl ethers used as starting materials in the preparation of the new compounds of the present invention may be prepared by any of the various methods described in my copending application, Serial No. 531,639, filed April 18, 1944, now Pat. No. 2,421,714.

What I claim as my invention is:

1. A compound of the formula,

where R1 and R2 are members of the class consisting of hydrogen, alkyl'r'adi'cals containing-1 to 2 carbon atoms and alkoxy radicals containing-1- to 2 carbon atoms, R: and R4 are members of the class consisting of alkyl radicals containing 1 to 3 carbon atoms inclusive and further members where R3 and R4 taken with-N form a saturated six-memberedheterocyclic ring, R5 is a"- member of the class consisting of hydrogen,

phenyl and lower alkyl radicals, Re is a member of the class consisting of alkyl radicals containing 1 to 10 carbon atoms inclusive, and aralkyl radicals and X is a member of the class consisting of chlorine, bromine and iodine atoms.

2. A compound of the formula,

Q Cy

cHo-cmomN' R4 O R. Ina-c.

where R: and R4 are members of the. class con+ sisting of alkyl radicals containing 1 to 3 carbonatoms inclusive and further members where R: and R4 taken with N form a saturated sixmembered heterocyclic ring, R5 is a member of the class consisting of hydrogen, phenyl and lower alkyl radicals, R6 is an alkyl radical containing 1 to 10 carbon atoms inclusive and X is a member of the class chlorine, bromine and iodine.

3. A compound of the formula,

C] CH;

CEO-CHzCHzN 5. A compound of the formula,

6. Process for obtaining a compound of the formula,

7 which comprises. reacting a compound of the formula,-

in a substantially anhydrous, inert organic solvent where R1 and R2 are members of the class consisting of hydrogen, alkyl radicals containing 1 to 2 carbon atoms and alkoxy radicals containing 1 to 2 carbon atoms, R3 and. R4 are members of the class consisting of alkyl radicals containing 1 to 3 carbon atoms inclusive and further members where R3 and R4 taken with -N form a saturated six-membered heterocyclic ring, R5 is a member of the class consisting of hydrogen, phenyl and lower alkyl radicals, R6 is a member of the class consisting of alkyl radicals containing 1 to 10 carbon atoms inclusive, and aralkyl radicals and X is a member of the class consisting of chlorine, bromine and iodine atoms.

7. Process for obtaining a compound of the formula,

which comprises reacting n-butyl chloroacetate with B-dimethylaminoethyl benzhydryl ether in a substantially anhydrous, inert organic solvent.

8. Process for obtaining a compound of the formula,

CHO-CHaCHzN OCHZCH;

8 which comprises reactin ethyl bromoacetate with fi-dimethylamindethyl benzhydryl ether in a substantially anhydrous, inert organic solvent.

9. Process for obtaining a compound of th formula,

which comprises reacting ethyl a-bromopropion ate with fi-dimethylaminoethyl benzhydryl ether in a substantially anhydrous, inert organic solvent.

10. A compound of the formula,

GEORGE RIEVESCHL, J'R.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,949,046 Hartmann et al. Feb. 27, 1934 2,297,221 Huttenlocher Sept. 29, 1942 2,387,447 Hofimann et al. Oct. 23, 1945 OTHER REFERENCES Bovet et al.: Chem. Abstracts, vol. 31 (1937), page 3988.

Dongen: Chem. Abstracts, vol. 35 (1941),

' pages 8099-8100. 

